Cobalt(II)-Mediated Three-Component Synthesis of 1,3,4-Oxadiazoles

Author: ChemistryViews
Published On: May 31, 2023
Copyright: Wiley-VCH GmbH

Multicomponent reactions can combine three or more reagents into one desired product. This can be useful, e.g., in drug development to obtain a range of structurally diverse drug candidates by varying the components. Isocyanides are often used in multicomponent reactions, and there are examples of transition-metal-catalyzed reactions that involve a nitrene transfer using azides and isocyanides, giving carbodiimides (R–N=C=N–R’). This usually requires catalysts based on expensive noble metals. Cobalt could be a useful, abundant alternative.

Jordy M. Saya, Romano V. A. Orru, Maastricht University, The Netherlands, Bert U. W. Maes, University of Antwerp, Belgium, and colleagues have developed a cobalt(II)-mediated three-component synthesis of 1,3,4-oxadiazol derivatives (general product structure pictured) from sulfonyl azides, N-isocyaniminotriphenylphosphorane (NIITP), and carboxylic acids. The team reacted different arene- or alkanesulfonyl azides with a broad range of aliphatic carboxylic acids and NIITP, using CoCl₂ as a mediator and MeCN as the solvent at 60 °C. Catalytic amounts of CoCl₂ only promoted the reaction with the desired selectivity when sterically hindered carboxylic acids were used; the team used a stoichiometric amount for other cases.

The desired 5-substituted-N-sulfonyl-1,3,4-oxadiazol-2(3H)-imines were obtained in yields of 22–82 %, depending on the substrates. The team proposes a reaction mechanism that involves the in-situ generation of a carbodiimide via a nitrene transfer, followed by addition of the carboxylic acid. Finally, an intramolecular aza-Wittig reaction gives the product. The products can be converted to 1,3,4-oxazol-2-amines, which can be used in further transformations.